Transcript HIV - Ronna

Introduction to HIV
AIM
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Epidemiology
Testing for HIV infection
Natural history of disease
When to start ART (guidelines/trends in the field)
Antiretroviral agents
Common toxicities
Opportunistic infections
OI prophylaxis
Global summary of the AIDS epidemic, 2008
Number of people
living with HIV in
2008
People newly
infected
with HIV in 2008
AIDS-related
deaths
in 2008
December 2009
Total
Adults
Women (aged 15 and
above)
Children under 15 years
33.4 million [31.1 – 35.8]
31.3 million [29.2 – 33.7]
Total
Adults
Children under 15 years
2.7 million [2.4 – 3.0]
2.3 million [2.0 – 2.5]
430 000 [240 K – 610K]
Total
Adults
Children under 15 years
2.0 million [1.7 – 2.4]
1.7 million [1.4 – 2.1]
280 000 [150 K – 410 K]
15.7 million [14.2 – 17.2]
2.1 million [1.2 – 2.9]
Case
• 23-year old woman presents to Emergency
Department with one week history of fever,
malaise, myalgias, headache and sore throat
• Five days PTA she noted the onset of a new
non-pruritic rash, on her face, torso,
extremities
• Two days PTA developed mouth sores that
were so painful she was unable to eat or drink
• PMH- negative
• Soc Hx- sexually active, single, in grad school
Case
• Physical Examination in ED
T 40oC. BP 104/76 P 108 R 20
Appears unwell
HEENT: Multiple oral ulcerations
Non-exudative pharyngitis
Multiple cervical nodes (slightly tender)
Diffuse maculopapular Rash
Case
• Laboratory data in ED
• H/H12/36
• WBC 3100 (65 segs, 25 lymphs, 6 atyp
lymphs, 4 monos)
• Platelets 71,000
• ALT 124, AST 75
• Urine drug screen negative
• All other labs normal
Differential Diagnosis
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Infectious Mononucleosis
CMV
HIV
Enterovirus- Coxsackie
Adenovirus
Streptococcal pharyngitis
Arcanobacterium hemolyticum
Syphilis
Principles of testing
• HIV infected patients produce antibodies
which recognize HIV proteins
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ELISA
Western Blot
Immunofluorescence
Radioimmunoprecipitation
Figure 6
Proteins Detected by HIV Western Blot
R
tat
pol
5’
U5
IN PRO
p17 p24
gag
HIV-1
}gp160/120{
p61POL
p55GAG
p51POL
gp41ENV
rev
3’
RT
vif vpr
vpu env gp120
env gp41
nef
U3
R
HIV-2
}gp135/120ENV{
p61POL
p55GAG
p51POL
p24GAG
gp36ENV
p31POL
p30GAG
p17GAG
p18GAG
p31POL
Interpretation of Western Blot
– Positive: ANY Two: p24, gp41, gp160/120
– Negative: NO positive bands
– Indeterminate: the remainder
• Isolated p24 band most common indeterminate
• Isolated gp160/120 band suspicious for early
infection
• A 38 year old multiparous nurse is evaluated because of an abnormal ELISA for
HIV when she attempted to donate blood. A follow up Western Blot analysis
has an indeterminate result. The patient is asymptomatic. She and her
husband have a monogamous relationship and neither have used illicit drugs.
Patient has never received a blood transfusion, and reports a needle stick
injury approximately 8 years ago from an HIV negative individual. Her physical
examination is normal, her CD4 count is normal, but her plasma viral load is 82
copies/ml. Which of the following is the most appropriate management at this
time?
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Recheck the plasma viral load now
Recheck the HIV serologic study in 3 months and 6 months
Begin HAART
Begin HAART if her CD4 count drops to <350/µL
WB Interpretation
Indeterminate
False Negative
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Window period
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Common variable immunodeficiency
NOT Subtype
– Newest assays should identify even O
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Infections (HIV-2 , HTLV-I, schisto)
Neoplasms
Dialysis
Ethnicity-Africans
Thyroiditis
Elevated Bilirubin
Rheumatologic diseases
Multiple pregnancy
Immunization (Tetanus, HIV)
Nephrotic proteinuria (massive)
Error in laboratory
HIV Infection Profile
rev
5’
R
tat
pol
U5
IN PRO
p17 p24
gag
3’
RT
vif vpr
vpu env gp120
env gp41
nef
U3
R
Anti-Env
antibody
Relative
Level
HIV RNA
Detection
limit
P24 antigen
Time Post-Infection
Natural history of the disease
• Seroconversion- Median time from exposure
to antibody-63 days (4 -10 wks)
• Clinical latent period
• Average rate of decline of CD4 cells after 1 yr
is 50 cells (range- 30-90)- correlated with the
viral load
• PGL
• Early symptomatic HIV infection
• AIDS
HIV Transmission Factors
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Stage of the disease
Viral load
STD
Genital lesions
Frequency of unprotected sex
Circumcision
Case
• A 35 year old asymptomatic male with a CD4 count of
325, viral load of 15,000 presents to the clinic for routine
evaluation. Hepatitis testing reveals that the patient has
a positive HBsAg, AST-80 and ALT of 85. Which of the
following is the most appropriate ART regimen
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Delay treatment till he is symptomatic
Begin azt/3tc/efv
Begin abc/3tc/efv
Begin tfv/ftc/efv
Response To Therapy
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Potency of antiretroviral therapy
Lower viral load
Higher CD4 count
Rapid reduction in plasma viral load in
response to therapy
• Approximately 70% achieve this goal and 80%
of patients in clinical trial settings achieve this
goal
Indications to start ART
CD4 BASED
IRRESPECTIVE OF CD4
COUNT
• ART is recommended for
patients with CD4 counts
between 350 and 500
• History of an AIDS defining
illness
• HIV associated nephropathy
• Concomitant hep B with
indications to initiate hep B
treatment
• Pregnancy
• 50% of the panel members
would start ART in patients
with CD4 counts greater
than 500
Probability of AIDS/Death
Life Cycle of HIV
Furtado MR et al. NEJM 1999;340:1614-22.
Life Cycle of HIV
Maturation
inhibitors
Fusion
Inhibitor
CCR5
INHIBITORS
PI
NRTI
NNRTI
INTEGRASE INHIBITORS
Furtado MR et al. NEJM 1999;340:1614-22.
Current Antiretroviral Medications
NRTI
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Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Zidovudine
Zalcitabine
Tenofovir
NNRTI
PI
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– soft gel
– hard gel
First
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Delavirdine
Efavirenz
Nevirapine
Second
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Etravirine
Amprenavir
Fosamprenavir
Atazanavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
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Tipranavir
Darunavir
Fusion inhibitor
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Enfurtivide
Integrase inhibitor
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Raltegravir
CCR5 inhibitor
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Maraviroc
Drugs in the pipeline
• NNRTI inhibitors
Rilpivirine
•Integrase inhibitors
• CXCR4
inhibitors
• Maturation
inhibitors
Elvitegravir
• CD4 blockers
•CCR5 inhibitors
Vicriviroc
Initial Treatment: Preferred
Components
NNRTI
• Efavirenz
PI
• Boosted Atazanavir
• Boosted Darunavir
INTEGRASE
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Raltegravir
NRTI
• Tenofovir
• Emtricitabine
Initial Treatment: Alternative
Components
NNRTI
• Nevirapine
PI
• Lopinavir/Ritonavir
• Boosted
Fosamprenavir
•Boosted Saquinavir
NRTI
• Abacavir
• Zidovudine
• Lamuvidine
Drugs with activity against hepatitis B
and HIV activity
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Tenofovir
Emtricitabine
Lamuvidine
Entecavir
NRTI
• Toxicities
– Bone marrow toxicity, macrocytic anemia, neutropenia
GI-nausea, vomiting-AZT
– General-headache, insomnia, asthenia-AZT
– Lactic acidosis-D4T>DDI>AZT>TFV/ABC
– Pancreatitis-DDI& D4T
– Peripheral neuropathy-DDI/D4T>AZT>TFV
– Lipoatrophy/lipodystrophy-D4T
– Myopathy (including cardiomyopathy)-AZT
– Hyperlipidemia-D4T>AZT>TFV/ABC
– Rapidly progressive ascending muscle weakness-D4T
NRTI
• Abacavir
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Abacavir hypersensitivity reaction
Fever, Rash
HLA type association with abacavir hypersensitivity
CAD
• Tenofovir
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Fanconi syndrome
Renal insufficiency
Dosage adjustment for Crcl<50
Bone abnormalities in monkeys and ?fetal risks
? osteopenia
Non-Nucleoside Reverse Transcriptase inhibitors
(NNRTI)
• Efavirenz
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CNS toxicity
Rash
Teratogenicity
False positive cannabinoid reaction
• Nevirapine
– Hepatotoxicity
– Highest risk in women whose CD4 count was greater than 250 at
the time of NVP initiation (11.0% vs 0.9%)
– Men with CD4 counts greater than 400 (6.3%vs 1.2%)
– Rash, with reports of TEN and SJS
Protease inhibitors
• Metabolic toxicities
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Hyperlipidemia/Hypertriglyceridemia-RTV
Hyperbilirubinemia-ATZ and IDV
Nephrolithiasis-IDV (a few case reports with ATZ)
Pyuria and Interstitial nephritis-IDV
Hyperglycemia-IDV and LPV/RTV
Diarrhea-LPV/RTV (cap)& NFV
CAD
Lipodystrophy
Drug drug interactions
Increased bleeding among hemophiliacs
PR interval prolongation-ATZ
Life threatening toxicities
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Abacavir hypersensitivity reaction
Lactic Acidosis with NRTI
Nevirapine related hepatotoxicity
Steven Johnson’s syndrome
Fusion inhibitors
• Injection site reaction almost universal
• Hypersensitivity reaction <1%- do not
rechallenge
• Increased rate of bacterial pneumonia
• A 35 year old female with HIV infection presents to the office. She was
diagnosed with PCP and at that time had a CD4 count of 92/µL, viral load105,000 copies/ml. AZT/3TC/EFV was initiated and 6 months post therapy
her CD4 count was 323/µL and her VL was ND. Approximately 1 year ago
she started missing appointments and 4 months prior her VL was 878
copies/ml and today her CD4 count is 300/µL and her VL is 5375
copies/ml. She remains asymptomatic. Which of the following is the most
appropriate management?
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Continue the current regimen
Substitute Nevirapine for Efavirenz
Add Nevirapine to the current regimen
Order an HIV genotype resistance assay
Recommend a drug holiday until she becomes symptomatic.
DHHS guidelines
• Monitoring of therapy
– Average gains- 50-150 cells/first year and 50- 100
cells/year (assuming viral control) thereafter until
a set point is reached
– Viral load suppression to below undetectable
should be achieved in 16-24 weeks in an ARV
naïve patient
– A 1 log decline in viral load in 2-8 weeks
– Viral suppression in 12-24 weeks
Pathogen
Indication
Preferred
Alternative
PCP
CD4<200,
oropharyngeal
candidiasis
Bactrim DS qd
Bactrim SS qd
Bactrim 1 DS triweekly
Dapsone
Aero-pentamidine
Atovaquone
Toxoplasmosis
CD4<100
Pos Toxo serology
Bactrim DS qd
Bactrim 1 SS qd
Dapsone+pyrimethamine
and leucovorin
Atovaquone/pyrimethamin
e/leucovorin
M.tuberculosis
TST>5mm
INH-300 mg po
Exposure to active TB qd
Prior pos untreated
TST
Rifampin-600 mg po qd
M.Avium
intracellulare
CD4<50
Rifabutin-300 qd
Azithro-1200 q
weekly
Claritho-500 bid
Opportunistic Infections
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Fever and Pulmonary infiltrate
CNS manifestations
Ophthalmologic manifestations
Diarrhea
Fever and Pulmonary infiltrate
• A 32 year old male presents to the clinic with
a 2 week history of non-productive cough,
worsening SOB and fever. The patient was
recently diagnosed with HIV and his CD4
count is 150 cells/µL.
• O/E- HR-100, RR-22, T-100, Pulse ox-85% RA.
• RS- examination reveals a few scattered rales
and rhonchi.
Differential Diagnosis
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PCP- the most commonly diagnosed OI in North America
M.tuberculosis
Community acquired pneumonia
C.neoformans
H.capsulatum
C.immitis
R.equi
Atypical Mycobacteria (M.kansasii)
HSV
CMV
KS
Malignancies
Case
• A 40 year female is bought in by her family.
Over the past few weeks her family has
noticed that she has been forgetful, lethargic
and confused. The patient has a CD4 count
of 35 and has not been on ART or
prophylaxis.
• Examination reveals a right sided
hemiparesis and VII nerve palsy
Differential Diagnosis By Presenting Symptoms,
Exam Findings
Focal
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Toxoplasmosis
Lymphoma
PML
Cryptococcoma
VZV
Meningovascular
syphilis
Other (TB, fungal)
Nonfocal
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Cryptococcal meningitis
CMV encephalitis
AIDS dementia
Lymphomatous
meningitis
- Other (TB, fungal)
Is This CNS Toxoplasmosis?
Factors that lessen the likelihood:
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On TMP-SMX or other prophylaxis
CD4 count > 100/μl
Negative serologies
Solitary lesion on MRI (multiple and bilateral lesions more
c/w toxo)
- No contrast enhancement
- No MRI improvement on 2-3 weeks of therapy
- Uptake on SPECT
Primary AIDS-Related CNS Lymphoma
 Mean CD4 = 30/μl
 EBV associated
 RARE among HIV negative
patients about 2% of AIDS
patients
 Evolution: 2-8 weeks
 Survival after diagnosis is
usually limited to months
 PCR of CSF is usually positive
for EBV
Case
• 32 year old african american male last
documented CD4 count of 10 presents to the
clinic with symptoms of lethargy, headache
and a skin rash. O/E- he is awake, but appears
minimally lethargic, there is no neck stiffness.
CSF exam-reveals a WBC count of 3, protein100, glucose-30.
Case
• A 35 year old AA male with a CD4 count of 65 presents to
the clinic with c/o progressive loss of vision and left sided
hemiparesis. A LP and MRI are performed. PCR of the CSF
is positive for JC virus. Which of the following is the most
appropriate treatment for this patient
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1-Start acyclovir
2-Start radiation and dexamethasone
3- Start sulfadiazine and pyrimethamine
4-Start HAART
• A 40 year old male with AIDS presents with a 1 days history of blurred
vision and a several hour history of acute loss of vision in the right eye. On
physical examination, vitals signs are normal. Pupils are equal and readily
reactive to light. Examination of the right fundus shows a localized area of
hemorrhagic necrosis of the fovea. The remainder of the examination is
normal. There are no exudates and no uveal disorders. After hospitalizing
the patient, which one of The following intravenous agents is most
appropriate?
Bactrim
Acyclovir
Gancyclovir
Penicllin
A corticosteroid
Case
• A 35 year old male with a CD4 count of 45
presents to the clinic with a 1 week history of
blurred vision, floaters in his right eye. There is
no pain or photophobia, external examination
is normal, fundoscopy reveals.
http://hivinsite.ucsf.edu/InSite
Case
• Which one of the following antivirals would
you like to use
– Valgancyclovir
– Gancyclovir
– Acyclovir
– Valacyclovir
Case
• A 45 year old HIV positive male whose CD4
count is 78 presents to the clinic with c/o
diarrhea. The diarrhea is non-bloody, painless.
He denies fevers. He states that his he recently
acquired a puppy. His labs reveal normal
electrolytes and a Hb-12.5. His serum alkaline
phosphatase is also within normal limits. Stool
cultures are negative
Protozoal Agents positive on AFB staining
Isospora Cyclosp Cryptospo Microsporid
ora
ridium
ium
Size (μ)
20-30
Mod afb
Positive Positive Positive
Therapy Tmp-smx,
8-10
Tmp-smx,
cipro,
cipro
pyrimetha
mine
4-6
HAART,
paromomycin,
nitazoxinide
1-5
Negative
albendazole
Case
• A 18 year old male previously treated for TB
with ATT was recently diagnosed with HIV. He
is started on an AZT/3TC/Nevirapine based
regimen. Approximately 3 weeks after starting
ART he presents to the clinic with worsening
SOB. His CD4 count at ART initiation was 55
cells/µL and viral load is 85,000 copies/ml. His
viral load at presentation was 85 copies/ml.
Immune Reconstitution Inflammatory Syndrome
(IRIS)
– Seen after HAART with immune recovery
– M.tuberculosis, Cryptococcus, CMV, MAC, PML,
– Manifest with rheumatologic manifestations as
well as Graves disease
– Continue HAART and treat underlying infection if
possible
– Sometimes need steroids to decrease
inflammation
References
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Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected
adults and adolescents. Department of Health and Human Services.. Available at
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentsGL.pdf.
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Clotet B et al Lancet 2007;369:1169-1178Efficacy and safety of darunavir-ritonavir at week 48 in treatment experienced
patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomized trials.
The stages and natural history of HIV infection J. Bartlett-Uptodate
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SMART study group NEJM 2006;355:2283-2296 CD4+ Count-Guided Interruption of Antiretroviral Treatment
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Cooper D et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1
integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses
and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105aLB.
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Steigbigel R et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1
integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses
and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105bLB.
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Markowitz M, Nguyen BY, Gotuzzo E, et al. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel
HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients: 48-week results. Program
and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25,
2007; Sydney, Australia. Abstract TUAB104.
References
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Selzentry- prescribing information
http://media.pfizer.com/files/products/uspi_maraviroc.pdf, accessed aug 21,2007
HIV drug resistance database http://hivdb.stanford.edu accessed Aug 18,2007
Shafer RW Clinical Microbiology Reviews Apr 2002;15: 247-277 Genotype testing for Human
Immunodeficiency Virus type I drug resistance
Slides from the Personal Collection of Dr. Maldarelli
Principles and Practices of infectious Diseases
MKSAP 14
2002 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons
infected with the HIV virus http://www.aidsinfo.nih.gov/guidelines/Guideline accessed Aug 28,2009
Treating opportunistic infections among HIV infected adults and adoloscents- December
17,2004 http://www.aidsinfo.nih.gov/guidelines/Guideline accessed Aug 28,2008